To identify the clinical and epidemiological profile of cryptococcosis diagnosed at the University Hospital of the Federal University of Mato Grosso do Sul, Brazil, medical records of 123 patients admitted from January 1995 to December 2005 were analyzed. One hundred and four cases (84.5%) had HIV infection, six (4.9%) had other predisposing conditions and 13 (10.6%) were immunocompetent. Male patients predominated (68.3%) and their age ranged from 19 to 69 years (mean: 35.9). Most patients (73.2%) were born and lived lifelong in the state of Mato Grosso do Sul. Involvement of the central nervous system occurred in 103 patients (83.7%) and headache and vomiting were the most frequent symptoms. In 77 cases it was possible to identify the Cryptococcus species: 69 (89.6%) C. neoformans and eight (10.4%) C. gattii. Amphotericin B was the drug of choice for treatment (106/123), followed by fluconazole in 60% of cases. The overall lethality rate was 49.6%, being 51% among the HIV infected patients and 41.2% among the non-HIV infected (p > 0.05). Although cryptococcosis exhibited in our region a similar behavior to that described in the literature, the detection of an important rate of immunocompetent individuals and five C. gattii cryptococcosis in HIV-infected patients is noteworthy.